In the United States, chronic liver disease is the 12th leading cause of disease-related death, with approximately 28,000 people dying each year from chronic liver disease. In the US and Europe, liver cirrhosis is the most common cause of non-neoplastic death among hepatobilliary and digestive diseases. Furthermore, the fourth leading cause of death in urban American males is alcoholic liver disease. Chronic liver disease is characterized by a process of progressive destruction and regeneration of liver cells that leads to hepatic fibrosis and cirrhosis.
Hepatic fibrosis is a process that occurs when the liver is damaged. Such damage can be the result of viral activity (e.g., chronic hepatitis types B or C) or other liver infections (e.g., parasites, bacteria); exposure to chemicals (e.g., pharmaceuticals, recreational drugs, excessive alcohol, exposure to pollutants); autoimmune processes (e.g., autoimmune hepatitis); metabolic disorders (e.g., lipid, glycogen, cholesterol or metal storage disorders); or cancer growth (primary or secondary liver cancer). The principal cell type responsible for liver fibrosis is the hepatic stellate cell (HSC), a resident perisinusoidal cell that takes up vitamin A from circulation and stores it.
In the liver, fibrosis is not only the result of necrosis, collapse and scar formation but also the result of derangements in the synthesis and degradation of matrix by injured mesenchymal cells that synthesize the various components of the extracellular matrix (ECM). Hepatic fibrosis is a gradual process of increased secretion and decreased degradation of extracellular materials. It is believed that the process is initiated by damage to hepatic cells. Necrotic hepatic cells present after injury evoke a reaction of inflammatory cells which secrete mediators including cytokines that stimulate matrix producing cells. More particularly, the damage to hepatic cells leads to the activation and secretion of multiple cellular factors from Kupffer cells, the macrophages which line the liver sinusoids. These factors, along with the cellular factors secreted by damaged hepatic cells, thrombocytes, and endothelial cells of the hepatic sinusoid become activators of HSCs. Upon activation, the HSCs differentiate to proliferative, fibrogenic and contractile myofibroblasts, and, via self-secretion and parasecretion, the HSCs proliferate and synthesize a massive amount of ECM materials, which gradually accumulate and form fibrous masses in the liver. The myofibroblasts secrete procollagen, which accumulates as insoluble collagen after its terminal domains are cleaved by procollagen peptides, causing fibrosis. The collagen-specific chaperone, heat shock protein 47 (HSP47), facilitates collagen secretion by ensuring proper triple-helix formation of procollagen in the endoplasmic reticulum and has also been implicated in translational regulation of procollagen synthesis.
The ECM materials are of the following categories: collagens (type I, III, IV, V, VI, VII), glycoprotein (laminin, fibronectin, entactin, undulin, and elastin) and proteoglycans (chondroitin sulphate, dermatan sulphate, keratan sulphate, heparan sulphate and heparin). These ECM materials interact with cell surface receptors and macromolecules such as growth factors, collagens, fibronectin, laminin etc. Fibrosis develops after repeated and persistent injury that overcomes the ability of the liver to degrade the ECM matrix via degrading enzymes produced by fibroblasts, neutrophils and macrophages. The excessive ECM materials built up in the liver lead to derangement of the hepatic architecture and portal hypertension, and can produce the irreversible and detrimental rearrangement of the liver circulation known as cirrhosis. Cirrhosis is characterized by replacement of liver tissue by fibrous, scar tissue and regenerative nodules. These regenerative nodules are the result of a process in which damaged tissue tries to regenerate and this leads to the loss of liver function. Therefore, fibrosis is both a sign of liver damage and a major contributor to liver failure via progressive cirrhosis of the liver. Since fibrosis is a common development in a variety of chronic liver diseases, treatment and/or prevention of liver fibrosis is of great importance.